The present invention concerns a new method for preparing lysergic acid esters.
Lysergic acid esters are intermediates for the conventional production of pharmacologically active compounds and also of each other. Thus, the known lisuride hydrogen maleate (U.S. Pat. No. 3,251,846) can be prepared, via the intermediate stage of the azide, for example according to the process described by Zikan [V. Zikan et al., Coll. Czechoslov. Chem. Commun., 25:1922 (1960)], using any of the esters prepared by the process of this invention.
In general, an acid amide is prepared from the ester. However, it is also possible to conduct the inverse reaction, i.e., the conversion of an acid amide into the corresponding ester, in one step. For this purpose, the acid amide is dissolved in an alcohol and a strong acid is added thereto. In most cases, a high acid concentration is required, for example, by introducing hydrogen chloride for several hours. This reaction is ordinarily accomplished under boiling heat of the alcohol employed, in some cases even in a sealed tube (Weygand-Hilgetag, "Organisch-chemische Experimentierkunst" [Experimenting Art in Organic Chemistry] Leipzig 1970, p. 352).
On the other hand, it is also known that lysergic acid and its derivatives, especially the esters, are easily rearranged under strongly acidic conditions into entirely useless benz[c,d]indolines [A. Stoll and T. Petrzilka, Helv. Chim. Acta 36:1125 (1953)]. This poses a major problem in acid catalyzed reactions preparing or using such esters.
Alkaline saponification of lysergic acid amides likewise takes place under rather drastic conditions which 4-7N potassium hydroxide solution under heating. It does not yield pure lysergic acid which then would first have to be esterified in a second step (see DAS No. 2,610,859).